Mitoketoscins: Novel mitochondrial inhibitors for targeting ketone metabolism in cancer stem cells (CSCs)
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Bela Ozsvari1,2, Federica Sotgia1,2, Katie Simmons3, Rachel Trowbridge3, Richard Foster3,4 and Michael P. Lisanti1,2
1 Translational Medicine, School of Environment & Life Sciences, University of Salford, Greater Manchester, UK
2 The Paterson Institute, University of Manchester, Withington, UK
3 School of Molecular & Cellular Biology & Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, West Yorkshire, UK
4 School of Chemistry, Faculty of Mathematics and Physical Sciences, University of Leeds, West Yorkshire, UK
Michael P. Lisanti, email:
Richard Foster, email:
Keywords: ketone bodies, drug design, mitochondria, tumor-initiating cells, cancer stem-like cells
Abbreviations: OXCT1, 3-Oxoacid CoA-Transferase 1 (mitochondrial); ACAT1, Acetyl-CoA Acetyltransferase 1 (mitochondrial); vHTS, Virtual High-Throughput Screening
Received: July 11, 2017 Accepted: July 31, 2017 Published: September 24, 2017
Previous studies have now well-established that epithelial cancer cells can utilize ketone bodies (3-hydroxybutyrate and aceto-acetate) as mitochondrial fuels, to actively promote tumor growth and metastatic dissemination. The two critical metabolic enzymes implicated in this process are OXCT1 and ACAT1, which are both mitochondrial proteins. Importantly, over-expression of OXCT1 or ACAT1 in human breast cancer cells is sufficient to genetically drive tumorigenesis and/or lung metastasis, validating that they indeed behave as metabolic “tumor promoters”. Here, we decided to target these two enzymes, which give cancer cells the ability to recycle ketone bodies into Acetyl-CoA and, therefore, to produce increased ATP. Briefly, we used computational chemistry (in silico drug design) to select a sub-set of potentially promising compounds that spatially fit within the active site of these enzymes, based on their known 3D crystal structures. These libraries of compounds were then phenotypically screened for their effects on total cellular ATP levels. Positive hits were further validated by metabolic flux analysis. Our results indicated that four of these compounds effectively inhibited mitochondrial oxygen consumption. Two of these compounds also induced a reactive glycolytic phenotype in cancer cells. Most importantly, using the mammosphere assay, we showed that these compounds can be used to functionally inhibit cancer stem cell (CSC) activity and propagation. Finally, our molecular modeling studies directly show how these novel compounds are predicted to bind to the active catalytic sites of OXCT1 and ACAT1, within their Coenzyme A binding site. As such, we speculate that these mitochondrial inhibitors are partially mimicking the structure of Coenzyme A. Thus, we conclude that OXCT1 and ACAT1 are important new therapeutic targets for further drug development and optimization. We propose that this new class of drugs should be termed “mitoketoscins”, to reflect that they were designed to target ketone re-utilization and mitochondrial function.
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